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While PKS catalysis is mostly based on fatty acid biosynthetic principles, polyketides can be further diversified by post\u2010PKS enzymes. Here, we characterized a remarkably versatile <jats:italic>trans<\/jats:italic>\u2010acyltransferase (<jats:italic>trans<\/jats:italic>\u2010AT) PKS from <jats:italic>Serratia<\/jats:italic> that builds structurally complex macrolides via more than ten functionally distinct PKS modules. In the oocydin PKS, we identified a new oxygenation module that \u03b1\u2010hydroxylates polyketide intermediates, a halogenating module catalyzing backbone \u03b3\u2010chlorination, and modular <jats:italic>O<\/jats:italic>\u2010acetylation by a thioesterase\u2010like domain. These results from a single biosynthetic assembly line highlight the expansive biochemical repertoire of <jats:italic>trans<\/jats:italic>\u2010AT PKSs and provide diverse modular tools for engineered biosynthesis from a close relative of <jats:italic>E.\u2005coli<\/jats:italic>.<\/jats:p>","DOI":"10.1002\/anie.202116614","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T16:34:52Z","timestamp":1642005292000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Modular Halogenation, \u03b1\u2010Hydroxylation, and Acylation by a Remarkably Versatile Polyketide Synthase"],"prefix":"10.1002","volume":"61","author":[{"given":"Franziska","family":"Hemmerling","sequence":"first","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy A.","family":"Meoded","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Fraley","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah A.","family":"Minas","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cora L.","family":"Dieterich","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rust","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Ueoka","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"},{"name":"School of Marine Bioscience Kitasato University  1-15-1, Kitazato, Minami-ku Sagamirhara-shi Kanagawa 252-0373 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Jensen","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Eidgen\u00f6ssische Technische Hochschule (ETH) Zurich  Vladimir-Prelog-Weg 4 8093 Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J. 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